The overarching purpose of this project is to advance our understanding ofthe influence of novel membrane associated steroid receptors on multiple phases of breast cancer progression. Progesterone is a key regulator of the membrane-associated steroid receptors and the importance of progesterone with respect to breast cancer etiology is highlighted by data from the Women's Health Initiative (WHl) randomized trials indicating that while use of combined estrogen and progestin menopausal hormone therapy (CHT) increases risk of breast cancer, use of estrogen alone does not. Dr. Li and his colleagues led the first of many subsequent studies to document that the risk of breast cancer associated with exogenous progestin use is primarily restricted to a more substantial increase in the risk of breast cancers of a lobular histologic type. However, the biological mechanisms underlying the strong relationship between progestin use and lobular breast cancer risk are essentially unknown. The findings from our population-based breast cancer studies (Drs. Porter and Li) and from in vitro studies in Dr. Ashley's laboratory identifying the presence and importance ofthe MPRs and CXCL12 and its receptor, CXCR4 in hormone-regulated reproductive pathways, lead us to hypothesize that both membrane associated receptors and metastatic chemoattractants, such as hormone-regulated CXCL12 and CXCR4, contribute to the differential impact of CHT use on risks and biology of lobular vs. ductal breast cancer. We plan to evaluate the contribution of membrane progesterone and estrogen receptor expression and downstream effects in relation to E+P use and histological subtype in well characterized ILC and IDC tumors from a large ongoing population-based study. Whole genome gene expression will be assessed in a subset of the lLC and IDC tumors to identify and characterize new factors and pathways relevant to the relationship between progesterone and breast cancer. This study will provide vital information relevant to breast cancer etiology and could lead to the identification of novel prevention and therapeutic targets. This project will also increase the capacity of NMSU to conduct competitive research through providing training on state ofthe art molecular techniques such as the DASL assay. Additionally, it partners a junior scientist. Dr. Ryan Ashley at NMSU, with two senior FHCRC scientists (Drs. Porter and Li) who will contribute directly to Dr. Ashley's career development.